Physical activity (PA) may be therapeutic for people with severe mental illness (SMI) who generally have low PA and experience numerous life style-related medical complications. We conducted a meta-review of PA interventions and their impact on health outcomes for people with SMI, including schizophrenia-spectrum disorders, major depressive disorder (MDD) and bipolar disorder. We searched major electronic databases until January 2018 for systematic reviews with/without meta-analysis that investigated PA for any SMI. We rated the quality of studies with the AMSTAR tool, grading the quality of evidence, and identifying gaps, future research needs and clinical practice recommendations. For MDD, consistent evidence indicated that PA can improve depressive symptoms versus control conditions, with effects comparable to those of antidepressants and psychotherapy. PA can also improve cardiorespiratory fitness and quality of life in people with MDD, although the impact on physical health outcomes was limited. There were no differences in adverse events versus control conditions. For MDD, larger effect sizes were seen when PA was delivered at moderate-vigorous intensity and supervised by an exercise specialist. For schizophrenia-spectrum disorders, evidence indicates that aerobic PA can reduce psychiatric symptoms, improves cognition and various subdomains, cardiorespiratory fitness, whilst evidence for the impact on anthropometric measures was inconsistent. There was a paucity of studies investigating PA in bipolar disorder, precluding any definitive recommendations. No cost effectiveness analyses in any SMI condition were identified. We make multiple recommendations to fill existing research gaps and increase the use of PA in routine clinical care aimed at improving psychiatric and medical outcomes.

MicroRNAs are key regulators of transcriptome plasticity and have been implicated with the pathogenesis of brain diseases. Here, we employed massive parallel sequencing and provide, at an unprecedented depth, the complete and quantitative miRNAome of the mouse hippocampus, the prime target of neurodegenerative diseases such as Alzheimer's disease (AD). Using integrative genetics, we identify miR-34c as a negative constraint of memory consolidation and show that miR-34c levels are elevated in the hippocampus of AD patients and corresponding mouse models. In line with this, targeting miR-34 seed rescues learning ability in these mouse models. Our data suggest that miR-34c could be a marker for the onset of cognitive disturbances linked to AD and indicate that targeting miR34c could be a suitable therapy.

During the last decades, schizophrenia has been regarded as a developmental disorder. The neurodevelopmental hypothesis proposes schizophrenia to be related to genetic and environmental factors leading to abnormal brain development during the pre- or postnatal period. First disease symptoms appear in early adulthood during the synaptic pruning and myelination process. Meta-analyses of structural MRI studies revealing hippocampal volume deficits in first-episode patients and in the longitudinal disease course confirm this hypothesis. Apart from the influence of risk genes in severe psychiatric disorders, environmental factors may also impact brain development during the perinatal period. Several environmental factors such as antenatal maternal virus infections, obstetric complications entailing hypoxia as common factor or stress during neurodevelopment have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes. In major depression, psychosocial stress during the perinatal period or in adulthood is an important trigger. In animal studies, chronic stress or repeated administration of glucocorticoids have been shown to induce degeneration of glucocorticoid-sensitive hippocampal neurons and may contribute to the pathophysiology of affective disorders. Epigenetic mechanisms altering the chromatin structure such as histone acetylation and DNA methylation may mediate effects of environmental factors to transcriptional regulation of specific genes and be a prominent factor in gene-environmental interaction. In animal models, gene-environmental interaction should be investigated more intensely to unravel pathophysiological mechanisms. These findings may lead to new therapeutic strategies influencing epigenetic targets in severe psychiatric disorders.